Abstract
Rearrangements involving the RUNX1 gene account for approximately 15% of balanced translocations in therapy-related acute myeloid leukemia (t-AML) patients and are one of the most common genetic abnormalities observed in t-AML. Drugs targeting the topoisomerase II (TOP2) enzyme are implicated in t-AML; however, the mechanism is not well understood and to date a single RUNX1-RUNX1T1 t-AML breakpoint junction sequence has been published. Here we report an additional five breakpoint junction sequences from t-AML patients with the RUNX1- RUNX1T1 translocation. Using a leukemia cell line model, we show that TOP2 beta (TOP2B) is required for induction of RUNX1 chromosomal breaks by the TOP2 poison etoposide and that, while TOP2 alpha (TOP2A) and TOP2B proteins are both present on RUNX1 and RUNX1T1 chromatin, only the TOP2B enrichment reached significance following etoposide exposure at a region on RUNX1 where translocations occur. Furthermore, we demonstrate that TOP2B influences the separation between RUNX1 and two translocation partners (RUNX1T1 and EVI) in the nucleus of lymphoid cells. Specifically, we identified a TOP2B-dependent increase in the number of nuclei displaying juxtaposed RUNX1 and RUNX1T1 loci following etoposide treatment.
Highlights
Therapy-related acute myeloid leukemia is becoming an increasingly important late effect following treatment for a primary malignancy due to increased survival rates in patients
Topoisomerase II (TOP2) poisons are used in many chemotherapy treatment protocols and consist of intercalating agents, such as mitoxantrone, and non-intercalating agents, such as etoposide (Cowell and Austin, 2012). Therapy-related acute myeloid leukemia (tAML) following TOP2 poison containing chemotherapy regimens are associated with recurrent balanced chromosome translocations involving the RUNX1 (AML1), RUNX1T1 (ETO), MLL, PML, and RARA loci
Etoposide-induced chromosomal breaks in the MLL locus are preferentially dependent on TOP2 beta (TOP2B) (Cowell et al, 2012)
Summary
Therapy-related acute myeloid leukemia (tAML) is becoming an increasingly important late effect following treatment for a primary malignancy due to increased survival rates in patients. TAML following TOP2 poison containing chemotherapy regimens are associated with recurrent balanced chromosome translocations involving the RUNX1 (AML1), RUNX1T1 (ETO), MLL, PML, and RARA loci. TOP2 enzymes catalyze the inter-conversion of different topological forms of DNA by passing one double-stranded DNA duplex through a transient enzyme-bridged break in a second DNA duplex (Austin and Marsh, 1998). These enzyme-bridged breaks, termed cleavage complexes, occur at low steady-state levels in normal cells (Willmore et al, 1998). TOP2A is involved in chromosome condensation and segregation and TOP2B has been implicated in transcription (Lyu et al, 2006; Tiwari et al, 2012), including modulation of transcription by nuclear hormones, such as estradiol, androgen, and retinoic acid (Ju et al, 2006; McNamara et al, 2008; Perillo et al, 2008; Haffner et al, 2010; Williamson and Lees-Miller, 2011)
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